Cytokines are generic terms for designating biologically active hormone-like proteins (interleukins, interferons, tumor necrosis factor, growth factors) that mediate their effects through a superfamily of receptors. Cytokines and their receptors constitute a powerful control network by which cells signal and coordinate cell proliferation and differentiation, cell death and survival. Cytokines are low molecular weight peptides having very potent biological activity. Their mechanism of action is generally autocrine and paracrine and act by ultimately regulating gene expression.
Cytokines and their receptors are thus implicated in major diseases. They regulate hematopoiesis, immunity and development of the nervous system. Most of all, they contribute to the development of afflictions such as cancer, inflammatory and autoimmune reactions, asthma, allergy, thrombosis, vascular diseases and septic shock by influencing aberrant or overexpressing genes leading to diseases. Cytokines and growth factors mediate tightly regulated biological effects in order to ensure proper control and functioning of the immune system. Therefore, cytokines are also involved in pathological conditions such as inflammation (e.g. rhumatoid arthritis) and tissue degeneration. Diseases which may develop or progress as a result of defects in cytokine or growth factor mediated cell signaling have a high prevalence in the population and are associated with significant morbidity and/or mortality. For these reasons cytokine receptors are important therapeutic target.
The treatments available for these pathologies are currently limited. They often result in high toxicity and secondary effects. The demand in the medical world for safer and more targeted therapies is therefore considerable.
The current approaches in the field of cytokines antagonists include the development of soluble receptors, monoclonal antibodies directed against cytokines, mimetics of cytokines, antisense techniques and kinases inhibitors. Few of these strategies have been successful in drug development, however. Nevertheless, certain antibodies targeting the ligand and the receptor, natural soluble receptor inhibitors (eg. IL1ra), and decoy soluble receptors have displayed interesting results. For instance, Trastuzumab (Herceptin, Roche) a monoclonal antibody which binds the HER-2/neu protein tyrosine kinase, and ZD1839 (Iressa, Astra-Zeneca), a small molecule which binds the EGF receptor are either in clinical trials or available for the treatment of certain diseases.
Non competitive antagonists of cytokines have also been described. In international application no. WO 93/14781 published in 1993, Fox describes the use of non-competitive peptides targeting intracellular domains of EGF. Intracellular domains are difficult to reach by peptides because of the barrier that the cell membrane constitutes.
Antagonists of the prior art are thus either competitive (e.g. soluble receptors, antibodies, cytokine mimetics), not very selective (e.g. tyrosine kinase inhibitors), costly to produce or difficult to apply in vivo (e.g. antisense). Because the ligand exceeds by far the concentration of the receptor, the concentration of competitive antagonists needed to inhibit the receptor is often substantial.
There is therefore a need for non-competitive, selective, extracellular and simple to identify, select and produce antagonists of cytokines.
The present invention seeks to meet these needs and other needs.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.